Hydroxymethylpolythiophene derivatives

ABSTRACT

Novel hydroxymethylthiophene derivatives and their medical use in treating or preventing inflammation and edema.

BACKGROUND OF THE INVENTION

This invention relates to hydroxymethylpolythiophene derivatives andtheir medical use.

Recent chemical and pharmacological activity studies on the extract ofthe Compositae Chinese herbs demonstrate that their unique chemicalcomponents of hydroxymethylpolythiophene derivatives possess usefulfunctions, such as anti-edema, anti-inflammatory, interferon-inducing,immunomodulating and anti-cancer activities.

No pharmacological activities of hydroxymethylpolythiophene orderivatives thereof have hitherto been reported.

SUMMARY OF THE INVENTION

One aspect of the present invention relates to a compound of theformula: ##STR1## in which n is 0; R is --CH₂ OR², --CH(R¹).OR²,--CH(O--Z)₂, or --COR³ ; R¹ is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ alkoxy, orC₁₋₆ acyloxy; R² is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ hydroxyalkyl, C₂₋₆alkoxyalkyl, tetrahydropyranyl, C₁₋₆ acyl, --CO--Y--COOH; and R³ is H,C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₁₋₆ alkoxy; wherein Z is C₁₋₆ alkyl, C₂₋₆alkenyl, or C₁₋₆ acyl; and Y is C₁₋₆ alkylidene, C₂₋₆ alkenylidene, orphenylene. Preferably, R is --CH₂ OR², --CH(R¹).OR², or --COR³ ; R¹ isC₁₋₆ alkyl; R² is H, C₁₋₆ acyl, or --CO--Y--COOH; and Y is --CH₂ --CH₂--, --CH═CH--, or phenylene.

Another aspect of this invention is a compound of formula (1), in whichn is 0; R is --CH(R¹)OCH₃, --CH(R¹).OR², --CH(O--Z)₂, or --COR³ ; R¹ isH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ alkoxy, or C₁₋₆ acyloxy; R² is H, C₂₋₆alkyl, C₂₋₆ alkenyl, C₁₋₆ hydroxyalkyl, C₂₋₆ alkoxyalkyl,tetrahydropyranyl, C₁₋₆ acyl, --CO--Y--COOH; and R³ is H, C₁₋₆ alkyl,C₂₋₆ alkenyl, or C₁₋₆ alkoxy; wherein Z is C₁₋₆ alkyl, C₂₋₆ alkenyl, orC₁₋₆ acyl; and Y is C₁₋₆ alkylidene, C₂₋₆ alkenylidene, or phenylene.Preferably, R is --CH(R¹).OR² or --COR³ ; R¹ is H; R² is H, C₁₋₆ acyl,or --CO--Y--COOH; and Y is --CH₂ --CH₂ --, --CH═CH--, or phenylene.

Also within the invention is a compound of formula (1), in which n is 1or 2; R is --CH(R¹).OR², --CH(O--Z)₂, or --COR³ ; R¹ is H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₁₋₆ alkoxy, or C₁₋₆ acyloxy; R² is H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₁₋₆ hydroxyalkyl, C₂₋₆ alkoxyalkyl, tetrahydropyranyl, C₁₋₆acyl, --CO--Y--COOH; and R³ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₁₋₆alkoxy; wherein Z is C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₁₋₆ acyl; and Y isC₁₋₆ alkylidene, C₂₋₆ alkenylidene, or phenylene. Preferably, n is 1; Ris --CH(R¹).OR² or --COR³ ; R¹ is H; R² is H, C₁₋₆ acyl, or--CO--Y--COOH; and Y is --CH₂ --CH₂ --, --CH═CH--, or phenylene.

C₁₋₆ hydroxyalkyl and C₁₋₆ akoxyalkyl refer to C₁₋₆ alkyl groupssubstituted with a hydroxyl functionality and an alkoxy functionality,respectively, e.g., --CH₂ CH₂ OH and --CH₂ CH₂₀ CH₃. Examples of C₁₋₆acyloxy include, but are not limited to, CH₃.CO.O-- and CH₃(CH₂)₄.CO--O--.

The term "alkyl", "alkenyl" or the alkyl or alkenyl moiety of asubstituted or a divalent alkyl or alkenyl group (e.g., hydroxyalkyl,alkoxy or alkenylidene) refers to both straight and branched carbonskeletons.

The term "phenylene" refers to p-, o- and m-phenylene. As an example,p-phenylene has the structure of ##STR2##

The term "alkylidene" refers to a divalent radical which has twohydrogens fewer than the alkane. Examples of C₁₋₆ alkylidene include,but are not limited to, CH₃ --CH₂ ═ and --CH₂ --CH₂ --. Similarly,examples of C₁₋₆ alkenylidene include, but are not limited to, --CH═CH--and --CH₂ CH═CHCH₂ --.

Set forth below are examples of compounds of this invention. (Me standsfor methyl and Et for ethyl.) ##STR3##

Note that a salt or an ester of any of the above-described compounds isalso within the scope of this invention.

Other features and advantages of the present invention will be apparentfrom the following drawings and description of the preferredembodiments, and also from the appending claims.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

CHEMICAL SYNTHESIS

The following synthetic methods, i.e., A through J, can be applied forthe preparation of hydroxymethyl-polythiophene derivatives of thisinvention. Note that symbols n, R, R¹, R³ and R² have been definedabove. New symbols (e.g., m or X) are defined when they first appear,and defined again to promote clarity whenever necessary.

A. As shown in the following reaction, α, α^(n) '-diacyl polythiophenederivatives (e.g., α, α^(n) '-diformyl polythiophene) can be readilyreduced to form α, α^(n) '-dihydroxymethyl polythiophene derivative.##STR4##

B. As shown in the following reaction, α-alkylhydroxymethyl-α^(n)'-alkoxymethyl polythiophene derivatives can be obtained by thereduction α-acyl-α^(n) '-alkoxymethyl polythiophene. ##STR5##

C. As shown in the following reaction, α, α^(n) '-dialkylhydoxymethylpolythiophene derivatives can be obtained by the Grignard reaction.##STR6## wherein R'=R¹ or R³.

D. As shown in the following reaction, α-alkyl hydroxymethyl-α^(n)'-alkoxymethyl polythiophene derivatives can also be obtained by theGrignard reaction. ##STR7##

E. As shown in the following reaction, symmetric α, α^(n)'-dialkoxymethyl polythiophene derivatives can be obtained by theUllmann coupling reaction. ##STR8## wherein m=1 or 2; and X=Br or I.

F. As shown in the following reaction, symmetric α, α^(n) '-dialkoxypolythiophene derivatives can be obtained by the condensation ofalkoxymethyl polythiophene under the catalysis of a palladium, nickel orcopper salt derivative. ##STR9## wherein A=H, Br, I or Li.

G. As shown in the following reaction, α, α^(n) '-dialkoxymethyl orα-monoalkoxymethyl-α^(n) '-monocarbonyl polythiophene derivatives can beobtained by the condensation of the lithium, magnesium, tin or zinc saltof α-alkoxymethyl polythiophene or α-monocarbony polythiophenederivative under the catalysis of a palladium, nickel or copper saltderivative. ##STR10## wherein each of m¹ and m² =1 or 2;

R", R'"=--CHR¹ OR² or --COR³ ;

V=MgX, Li, Sn(R°)₃, or ZnX;

X=Cl, Br, or I; and

R°=C₁₋₄ alkyl.

H. As shown in the following reaction, symmetric α, α^(n)'-dialkoxymethyl polythiophene derivatives can be obtained by theGrignard condensation of a dihalopolythiophene and lithium, magnesium,tin or zinc derivative of α-alkoxymethyl thiophene under the catalysisof a palladium, nickel or copper salt derivative. ##STR11## whereinV=MgX, Li, Sn(R°)₃, or ZnX;

X=Cl, Br, or I; and

R°=C₁₋₄ alkyl.

I. As shown in the following reaction, α-alkoxymethyl orα-hydroxymethyl-α^(n) '-formyl polythiophene derivative can be obtainedby the formylation of a α-hydroxymethyl polythiophene derivative.##STR12##

J. As shown in the following reaction, α-alkoxymethyl-α^(n) '-acylpolythiophene can be obtained by the ordinal acylation of α-alkoxymethylpolythiophene. ##STR13## wherein W=halogen or OH; and

R°=C₁₋₄ alkyl.

Without further elaboration, it is believed that one skilled in the artcan, based on the above description, utilize the present invention toits fullest extent. The following specific examples are, therefore, tobe construed as merely illustrative, and not limitative of the remainderof the disclosure in any way whatsoever.

EXAMPLE 1 Synthesis of 5,5'-dihydroxymethyl bithiophene

(a) 5-hydroxymethyl-5'-formyl bithiophene (0.2 g) was dissolved inethanol (50 ml). NaBH₄ (0.1 g) was added at room temperature, andstirred for 1 hour. The solution was monitored by thin layerchromatography to determine whether the reaction was completed. H₂ O (50ml) was added and the ethanol was removed under reduced pressure. Afterfiltration, the solid product was recrystallized. The yield was almostquantitative and the melting point of the product was 158°-160° C.

Data of spectra:

¹ H NMR (D⁶ -acetone) 7.03-6.87 (m, 4H, protons of thiophene) 4.73 (s,4H, --CH₂ OH)

IR (KBr) cm⁻¹ 3500-3300 (OH) 3050 2900, 2850 1453, 1415, 1360, 1230,1200, 1175 1055, 1025, 1002 880, 870, 795

Mass spectrum, m/e (relative intensity) 226 (M⁺, 100), 209 (M⁺ --OH, 73)

(b) 5-hydroxymethyl-5'-formyl bithiophene(0.6 g) was dissolved intetrahydrofuran ("THF") (30 ml), NaBH₄ (0.16 g) was added, and thesolution was stirred for 2 hours at room temperature. THF was removedunder reduced pressure. The white solid obtained was washed with waterand dried under reducing pressure. The yield was quantitative. Themelting point of the product was 155°-156° C.

(c) 5-hydroxymethyl-5'-formyl bithiophene (0.5 g) was reduced in ethanol(75 ml) with NaBH₄ (0.3 g). The mixture was stirred for 3 hours at roomtemperature. The solution was concentrated and n-hexane was added tocrystallize the white-powdered product. The crystal was filtered andwashed with water. The crystal was dried by reducing the pressure andthe yield was quantitative. The melting point of the product was155°-156° C.

(d) 2-hydroxymethyl-5-iodothiophene was refluxed with Cu powder indimethyl formamide ("DMF"). This Ullmann condensation also yielded avery low amount of 2,5-dihydroxymethyl bithiophene.

(e) The Ullmann condensation of 2-acetoxymethyl gave5,5'-diacetoxymethylbithiophene. 5,5'-dihydroxymethyl bithiophene wasobtained by alkaline hydrolysis and refined by column chromatography.The yield was about 20%.

EXAMPLE 2 Synthesis of 5,5'-diacetoxymethyl bithiophene

5,5'-dihydroxymethyl bithiophene (0.23 g), pyridine (1.2 ml) and aceticanhydride (0.3 ml) were mixed, stirred and kept overnight. Then themixture was extracted with ethylacetate. The pyridine and acetic acidwere removed by washing with weak base and weak acid, respectively.Silica gel powder was added into the ethyl acetate solution and thesolvent was removed under reduced pressure. Coated silica gel powder wasadded to the silica gel column and chromatographed. The eluant was ethylacetate/n-hexane (7/3). The white crystal thus obtained was furtherrecrystallized with ethyl acetate/n-hexane mixture. The melting point ofthe product was 60° C.

Data of spectra:

IR cm⁻¹ 1725 (C═O)

Mass spectrum, m/e (relative intensity) 310 (M⁺, 37) 251 (M⁺ --CH₃ CO₂,100) 192 (M⁺ -2 CH₃ CO₂, 34)

EXAMPLE 3 Synthesis of 5-hydroxymethyl-5'-formyl bithiophene

Phosphorus oxychloride ("POCl₃ ") (1 ml) was added into DMF (20 ml)slowly under nitrogen gas atmosphere in ice bath and stirred for 1 hour.The DMF solution (5 ml) of 5-hydroxymethyl bithiophene (0.5 g) wasdropped in slowly. The mixture was stirred for half an hour at roomtemperature, then the temperature was raised to 50° C. and was furtherstirred for 3 hours. The reaction solution was poured into potassiumcarbonate ice water solution. Then the solution was extracted with 100ml of ethyl acetate. The extract was washed with water and dried overanhydrous magnesium sulfate. The solvent was removed under reducedpressure. The residual solid was purified by column chromatography. Theeluant was ethyl acetate/n-hexane (3/7). The slightly yellowish productwas recrystallized with ethyl acetate/n-hexane mixture. The meltingpoint of the product was 123°-124° C. The yield was 85%.

Data of Spectra:

¹ H NMR 400 MHz (CDCl₃), δ value 9.91 (s, 1H, --CHO) 7.73-7.02 (m, 4H,protons of thiophene) 4.91-4.90 (d, 2H, --CH₂ OH)

IR (KBr) cm⁻¹ 3300 (OH) 1640 (C═O)

Mass spectrum, m/e (relative intensity) 224 (M⁺, 100) 207 (M+--OH, 57)195 (M+--CHO, 22)

EXAMPLE 4 Synthesis of 5-acetoxyethyl-5'-formyl bithiophene

5-hydroxymethyl-5'-formyl bithiophene (0.2 g) and pyridine (1 ml) weremixed together. Acetic anhydride (1 ml) was added slowly into themixture while stirring. Ethylacetate (200 ml) and water (50 ml) wereadded 2 hours later. The ethyl acetate layer was washed with weak base,weak acid and water. The product was concentrated and purified by columnchromatography. The eluant was ethyl acetate/n-hexane (1/9). Slightlyyellowish crystal was obtained. The melting point of the crystal was89°-91° C. The yield was 95%.

Data of Spectra:

¹ H NMR 400 MHz (CDCl₃), δ value 9.83 (s, 1H, --CHO) 7.64-7.01 (m, 4H,protons of thiophene) 5.20 (s, 2H, --CH₂ OAc) 2.08 (s, 3H, --COCH₃)

IR (KBr) cm⁻¹ 1740, 1660 (C═O)

EXAMPLE 5 Synthesis of 5-hydroxethyl-5"-formyl terthiophene

POCl₃ (1 ml) was added to DMF (30 ml) slowly under nitrogen stream inice bath condition. The solution was stirred for 1 hour and then DMFsolution (20 ml) of 5-hydroxymethyl terthiophene (0.5 g) was dropped inslowly. The mixture was stirred for half an hour at room temperature andthen the temperature was raised to 60° C. and stirred for further 2hours. The reaction solution was poured into ice aqueous potassiumcarbonate solution. The solution was extracted with 300 ml of ethylacetate and the extract was dehydrated with anhydrous magnesium sulfate.The solvent was removed under reduced pressure and the residual solidwas purified by column chromatography. The eluant was ethylacetate/n-hexane (3/7). The orange colored crystal was obtained and themelting point of the product was 176°-177° C. The yield was 80%.

Data of Spectra:

¹ H NMR 400 MHz (CDCl₃), δ value 9.86 (s, 1H, --CHO) 7.65-6.91 (m, 6H,protons of thiophene) 4.80 (s, 2H, --CH₂ OH.sub.)

IR (KBr) cm⁻¹ 3400 (OH) 1660 (C═O)

Mass spectrum, m/e (relative intensity) 306 (M⁺, 100) 289 (M⁺ --OH, 56)

EXAMPLE 6 Synthesis of 5,5"-dihydroxymethyl terthiophene

5,5'-diformyl terthiophene (0.6 g) was added into THF (30 ml). Thetemperature was raised to 50° C. until the solute was completelydissolved, then NaBH₄ (0.25 g) was added and stirred for 3 hours at 50°C. The solvent was removed under reduced pressure. Ethylacetate andwater were added to dissolve the residual solid. The ethyl acetate layerwas washed with water and dried over anhydrous magnesium sulfate. Theethyl acetate layer was filtered and concentrated to obtain slightlyyellowish solid (0.95 g). This was recrystallized from alcohol and themelting point of the product was 182°-183° C.

Data of Spectra:

¹ H NMR 400 MHz (CDCl₃), δ value 7.04-6.89 (m, 6H, protons of thiophene)4.79 (d, 4H, CH₂ OH) 1.51 (br. s., OH)

Mass spectrum, m/e (relative intensity) 308 (M⁺, 58) 306 (M⁺ -2H, 100)

EXAMPLE 7 Synthesis of 5-hydroxymethyl-5"-(1-hydroxypropyl) terthiophene

5-hydroxymethyl-5"-formyl terthiophene (0.5 g) was dissolved intoanhydrous THF (50 ml). A little excess of calculated amount of 2.0Methyl magnesium bromide were added to the THF solution under nitrogenatmosphere. The solution was stirred for 3 hours at room temperature.Aqueous ammonium chloride solution was added to hydrolyze the abovereaction solution to obtain the product. The product is collected,separated and purified by column chromatography. The eluant was ethylacetate/n-hexane (3/7) solution and concentrated to obtain orangepowdered solid (0.3 g). The melting point was 131°-132° C.

Data of spectra:

¹ H NMR 400MHz (CDCl₃), δ value 7.03-6.85 (m, 6H, protons of thiophene)4.79-4.78 (m, 3H, --CH₂ OH and ##STR14## 1.91-1.77 (m, 2H, --CH₂ CH₃)0.99-0.95 (t, 3H, --CH₃)

IR (KBr) cm⁻¹ 3400 (OH), 2900 (saturated CH)

EXAMPLE 8 Synthesis of 5-succinoyloxethyl-5'-formyl bithiophene

5-hydroxymethyl-5'-formyl bithiophene (0.63 g), pyridine (10 ml) andsuccinyl anhydride (0.12 g) were mixed together. The mixture was stirredat 40° C. Thin layer chromatography was applied to monitor the reaction.After the reaction was completed, diluted hydrochloric acid and ethylacetate were added. The ethyl acetate solution was washed with water toremove pyridine completely. Then the ethyl acetate layer was dehydratedwith anhydrous magnesium sulfate and filtered through silica gel layer.After removal of the solvent and the product was recrystallized withethyl acetate/n-hexane to give a slightly yellowish crystal (0.6 g). Themelting point was 127° C.

Data of spectra:

¹ H NMR 400MHz (CDCl₃), δ value 9.84 (s, 1H, --CHO) 7.65-7.02 (m, 4H,protons of thiophene) 5.25 (s, 2H, --CHO--) 2.72-2.64 (m, 4H, --COCH₂CH₂ CO--) 2.40 (br, OH)

IR (KBr) cm⁻¹ 3200-2500 (OH) 1730, 1705, 1650 (C═O)

EXAMPLE 9 Synthesis of 5,5'-disuccinoyloxymethyl bithiophene

5,5'-dihydroxymethyl bithiophene (0.5 g), pyridine (10 ml) and succinylanhydride (2 g) were mixed together. The mixture was stirred at 40° C.Thin layer chromatography was applied to monitor the reaction. After thereaction was completed, ethyl acetate was added to extract the product.The ethyl acetate layer was washed with diluted hydrochloric acid andwater in order to remove pyridine completely. The product was filteredthrough silica gel powder layer and recrystallized with ethylacetate/n-hexane. White crystal (0.45 g) was obtained. The melting pointof the crystal was 137° C.

Data of spectra:

¹ H NMR 400MHz (CDCl₃), δ value 7.00-6.90 (m, 4H, protons of thiophene)5.28-5.23 (m, 4H, --CH₂ O--) 4.78-4.75 (m, 4H, --CH₂ O--) 2.69-2.64 (m,8H, --CO--CH₂ CH₂ --CO--)

IR (KBr) cm⁻¹ 3600-2500 (OH) 1718, 1688 (C═O)

EXAMPLE 10 Synthesis of 5-ethoxymethyl terthiophene

5-formyl terthiophene (0.3 g) was dissolved in ethanol (10 ml) bystirring at room temperature. To the solution, 0.04 g of NaBH₄ wasslowly added. After the solution became clear in about 20 minutes,diluted hydrochloric acid was slowly added until bubbling stopped. Thestirring was continued for about 2 hours, followed by chloroformextraction and silica gel column chromatography (eluted by ethylacetate/n-hexane=1/19). The product was recrystallized withchloroform/ethyl acetate mixture to give a slightly yellowish crystal(melting point 76°-77° C.). The yield was about 41%.

The yield could be increased to 85% or higher by substituting absoluteethanol for alcohol and concentrated hydrochloric acid for dilutedhydrochloric acid. More specifically, 5-formyl terthiophene (0.2 g) wasfirst dissolved in absolute ethanol (15 ml) at room temperature. To thesolution, 0.03 ml concentrated hydrochloric acid/absolute ethanolmixture (0.3 ml conc. HCl in 10 ml absolute ethanol) was then added.After stirring for 2 hours, 0.8 g sodium bicarbonate (NaHCO₃) was addedand the stirring was continued for 0.5 hours followed by filtration. Theethanol was removed under reduced pressure. 5-ethoxymethyl terthiophenethus obtained was purified by silica gel chromatography.

Data of spectra:

¹ H NMR 400MHz (CDCl₃), δ value 7.20-6.87 (m, 7H, protons of thiophene)4,62 (s, 2H, --CH₂ OC₂ H₅) 3.55 (q, 2H, --CH₂ OCH₂ CH₃) 1.25 (t, 3H,--OCH₂ CH₃)

IR (KBr) cm⁻¹ 3050 (aromatic CH) 2971, 2852 (saturated CH) 1091(--C--O--)

Mass spectrum, m/e (relative intensity) 306 (M⁺, 100) 261 (M⁺ --OC₂ H₅,33)

BIOLOGICAL ACTIVITY

The anti-edema activity was tested according to the conventional toeedema method using carrageenan as pyrogen and indomethacin as controlinhibitory agent. See C. A. Winter, E. A. Risley and G. W. Nuss, Biol.Med., 111, 544 (1962); and A. P. Roszkowshi, W. H. Rooks II, A. J.Tomolonis and L. M. Miller, J. Pharmacol. Exp. Ther., 179, 114 (1971),both of which are hereby incorporated by reference.

In general, polythiophene derivatives of this invention have shownsignificant anti-edema activity. For example, the anti-edema effect ofdihydroxymethylbithiophene and its diacetate is shown in the Table 1.

                  TABLE 1                                                         ______________________________________                                        Anti-edema Effect of Polythiophene Derivatives*                                                     Dosage    Inhibition                                    Compound              (mg/kg)   rate (%)                                      ______________________________________                                         ##STR15##             10  50 100 200                                                                         26 34 37 41                                    ##STR16##             50 100 200                                                                             17 28 28                                       ##STR17##             50 100 200                                                                             32 36 38                                      ______________________________________                                         *A compound with an inhibition rate above 30% is considered to be also        antiinflammatory.                                                        

OTHER EMBODIMENTS

From the above description, one skilled in the art can easily ascertainthe essential characteristics of the present invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

For example, a pharmaceutical composition comprising one or more theabove-described polythiophene derivatives is also within the scope ofthe present invention. Thus, other embodiments are also within theclaims.

What is claimed is:
 1. A compound of the formula: ##STR18## in which nis 0;R is --CH(R¹)OCH₃, --CH(R¹).OR², CH(R¹).O(C₂ -C₆ alkyl),--CH(O--Z)₂, or --COR³ ; R¹ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ alkoxy,or C₁₋₆ acyloxy; each R² and R⁴, independently, is H, C₂₋₆ alkenyl, C₁₋₆hydroxyalkyl, C₂₋₆ alkoxyalkyl, tetrahydropyranyl, or --CO--Y--COOH; andR³ is H, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₁₋₆ alkoxy; wherein Z is C₁₋₆alkyl, C₂₋₆ alkenyl, or C₁₋₆ acyl; and Y is C₁₋₆ alkylidene, C₂₋₆alkenylidene, or phenylene provided that R and --CH(R¹).OR⁴ cannot bothbe CH2OH and further provided that when R is CHO, --CH(R¹).OR⁴ cannot beCH2OH; or a salt or an ester thereof.
 2. The compound of claim 1,wherein R is --CH(R¹).OR⁴ or --COR³ ; each R² and R⁴, independently, isH, or --CO--Y--COOH; and Y is --CH₂ --CH₂ --, --CH═CH--, or phenylene.3. The compound of claim 2, wherein R is --CH(R¹).OR⁴ and each R² andR⁴, independently, is H.
 4. The compound of claim 2, wherein R is--CH(R¹).OR² and each R² and R⁴, independently, is --CO--Y--COOH.
 5. Thecompound of claim 2, wherein R is --COR³ and each R² and R⁴,independently, is C₁₋₆ acyl or --CO--Y--COOH.
 6. The compound of claim 1of the following formula: ##STR19##